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Life sciences · Journal article
Small · September 23, 2026
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ABSTRACT Antibody‐drug conjugates (ADCs) have revolutionized HER2‐positive breast cancer treatment, yet resistance to next‐generation agents such as SHR‐A1811 (trastuzumab rezetecan) remains a major challenge arising from poor intratumoral delivery, enhanced DNA damage repair, and an immunosuppressive tumor microenvironment (TME). Here, we engineered HER2‐targeted AIE780‐A1811 nanoparticles (NPs) by covalently conjugating the mitochondria‐directed NIR photosensitizer AIE780 with SHR‐A1811 via EDC/Sulfo‐NHS‐mediated amide coupling. These core–shell NPs exhibit an optimal size for EPR‐mediated tumor accumulation, high photothermal conversion efficiency, and stable NIR fluorescence for real‐time imaging. Upon 660 nm irradiation, AIE780‐A1811 NPs generate robust ROS and potent photothermal effects, inducing tumor cell death and stimuli‐responsive SHR‐A1811 release to amplify DNA double‐strand breaks. Mechanistically, this combination therapy activates the NLRP3 inflammasome–GSDMD axis, driving immunogenic pyroptosis and the release of damage‐associated molecular patterns. Concurrently, it reprograms tumor‐associated macrophages from an M2‐like to an M1‐like phenotype, enhances CD8 + T cell infiltration, and reduces regulatory T cells, thereby remodeling the immunosuppressive TME. AIE780‐A1811 NPs demonstrate potent antitumor efficacy across SHR‐A1811‐resistant cell lines, patient‐derived organoids, and mouse xenografts, achieving near‐complete tumor regression with negligible systemic toxicity. This multimodal strategy integrating targeted chemotherapy, photothermal therapy, and immunomodulation offers a promising translational approach to overcome ADC resistance in refractory HER2‐positive breast cancer.